Eur Radiol DOI 10.1007/s00330-016-4255-0

CHEST

Preoperative staging of non-small cell lung cancer: prospective comparison of PET/MR and PET/CT Sang Min Lee 1,2,3 & Jin Mo Goo 1,2,4 & Chang Min Park 1,2,4 & Soon Ho Yoon 1,2 & Jin Chul Paeng 5 & Gi Jeong Cheon 5 & Young Tae Kim 4,6 & Young Sik Park 7,8

Received: 5 July 2015 / Revised: 25 January 2016 / Accepted: 27 January 2016 # European Society of Radiology 2016

Abstract Objectives To prospectively compare the accuracies of PET/ MR and PET/CT in the preoperative staging of non-small cell lung cancer (NSCLC). Methods Institutional review board approval and patients’ informed consents were obtained. 45 patients with proven or radiologically suspected lung cancer which appeared to be resectable on CT were enrolled. PET/MR was performed for the preoperative staging of NSCLC followed by PET/CT without contrast enhancement on the same day. Dedicated MR images including diffusion weighted images were obtained. Readers assessed PET/MR and PET/CT with contrast-

* Jin Mo Goo [email protected]

1

Department of Radiology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea

2

Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea

3

Present address: Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

4

Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

5

Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea

6

Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul, Korea

7

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

8

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

enhanced CT. Accuracies of PET/MR and PET/CT for NSCLC staging were compared. Results Primary tumour stages (n = 40) were correctly diagnosed in 32 patients (80.0 %) on PET/MR and in 32 patients (80.0 %) on PET/CT (P = 1.0). Node stages (n = 42) were correctly determined in 24 patients (57.1 %) on PET/MR and in 22 patients (52.4 %) on PET/CT (P = 0.683). Metastatic lesions in the brain, bone, liver, and pleura were detected in 6 patients (13.3 %). PET/MR missed one patient with pleural metastasis while PET/CT missed one patient with solitary brain metastasis and two patients with pleural metastases (P = 0.480). Conclusions This study demonstrated that PET/MR in combination with contrast-enhanced CT was comparable to PET/ CT in the preoperative staging of NSCLC while reducing radiation exposure. Key points • PET/MR can be comparable to PET/CT for preoperative NSCLC staging. • PET/MR and PET/CT show excellent correlation in measuring SUVmax of primary lesions. • Using PET/MR, estimated radiation dose can decrease by 31.1 % compared with PET/CT. Keywords Non-small cell lung cancer . PET/CT . PET/MR . TNM staging . PET

Abbreviation and acronyms NSCLC Non-small cell lung cancer 18 F-fluorodeoxyglucose FDG PET/ Positron emission tomography/computed CT tomography PET/ Positron emission tomography/magnetic MR resonance

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VIBE HASTE SPAIR DWI ADC TNM

Volume-interpolated breath-hold examination Half-Fourier acquisition single-shot turbo spinecho Spectral selection-attenuated inversion recovery Diffusion-weighted imaging Apparent diffusion coefficient Tumour, node, and metastasis

Introduction Accurate staging of lung cancer is a critical initial step for the appropriate selection of the optimal treatment strategy and in predicting the patients’ prognosis [1]. At present, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), which provides morphological as well as metabolic data of lung cancer, is widely accepted to be the first-line imaging tool for staging [2]. Indeed, it has been previously shown that the high diagnostic performance of PET/CT can lead to a significant decrease in the incidence of futile thoracotomies [3]. However, the staging of lung cancer with PET/CT still remains problematic owing to false-positives from the PET component and the low soft tissue contrast ability of CT. For instance, inflammatory or granulomatous lymph nodes can appear to be FDG-avid on PET/CT leading to false positive results [4] and poor visualization of brain metastases on PET/CT can result in false negatives [5]. Unfortunately, these difficulties result from the inherent limitations of PET/CT. In this context, the newly introduced PET/MR system has garnered attention as MRI with superior soft tissue contrast and dedicated sequences has the potential to compensate the shortcomings of PET/CT. Several studies [5–9] have reported that MRI can provide comparable performance to PET/CT in lung cancer staging and the PET information obtained from PET/MR was equivalent to that from PET/CT despite concerns over MR-based attenuation correction [9, 10]. As for the staging for lung cancer using PET/MR, Schwenzer et al. [9] demonstrated the feasibility of PET/MR compared with PET/CT although they did not utilize dedicated MR sequences and did not perform histopathological confirmation. On the contrary, however, Heusch et al. [11] recently reported that PET/MR using dedicated pulmonary MR imaging protocols did not provide advantages over PET/CT in thoracic staging in their review of 22 non-small cell lung cancer (NSCLC) patients. Yet, one thing we must consider is that in Heusch et al.’s study [11], analysis of distant metastasis was not performed. Given that detecting distant metastases in the brain and liver has been shown to be better on MR than PET/ CT [5], Heusch et al.’s study may not have fully addressed the

comparison between PET/MR and PET/CT. Furthermore, although a study by Yi et al. [12] reported that PET/MR was, in the majority of patients that were understaged by PET/CT, not able to provide the correct stage either, relative to the reference, they obtained coregistered PET/MR images using software, not simultaneous acquisition. Therefore, it still remains to be determined whether simultaneous PET/MR can offer better diagnostic performance in the staging of lung cancer compared with PET/CT. Thus, the purpose of our study was to prospectively compare the accuracies of whole-body PET/MR and PET/CT in the preoperative staging of NSCLC.

Materials and methods This prospective study was approved by the institutional review board of Seoul National University Hospital, and written informed consent was obtained from all patients. Study population From March 2013 to March 2014, patients with a biopsyproven or radiologically suspected lung cancer, which appeared to be resectable on chest CT, were prospectively enrolled in this study. Patients were excluded, if they had received any previous treatment for cancer or other malignancies, and if they were not eligible for curative surgery. In addition, pregnant women, patients under 18 years of age, and patients who were contraindicated for MRI (e.g., patients with pacemakers or claustrophobia), were also excluded. Of the 55 patients who were initially included, ten patients were excluded due to histological results other than NSCLC (small cell lung cancer, n = 2; tuberculosis, n = 2) or because subsequent surgical resection was not performed (radiation therapy, n = 3; follow-up loss, n = 2; refusal of surgery, n = 1). Finally, 45 patients (mean age, 62.9 years ± 9.9; range, 35-79 years) comprised our study population. There were 26 men (mean age, 63.8 years ± 10.4; range, 35-79 years) and 19 women (mean age, 61.6 years ± 9.4; range, 40-74 years). Mean intervals between PET/MR and surgery were 18.3 days (range, 5–68 days; median, 14.5 days). Image acquisition PET/MR imaging All patients fasted for at least 6 hours before intravenous administration of 18F-FDG at a dose of 5.2 MBq/kg of body weight. Radiation exposure of PET was estimated based on a method described in a previous study [13]. After FDG

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administration, patients rested for 60 minutes prior to imaging. Thereafter, PET/MR examinations were performed using a whole-body hybrid PET/MR system (Biograph mMR; Siemens Healthcare, Erlangen, Germany). The scan range of PET/MR was from the head to the midthigh using five or six bed positions. In each bed position, the coronal 3-D volume-interpolated gradient echo (VIBE) sequence for Dixon-based attenuation correction, coronal T1weighted turbo spin-echo sequence, axial T2-weighted halfFourier acquisition single-shot turbo spin-echo (HASTE) with spectral selection-attenuated inversion recovery (SPAIR) fat suppression, and axial 3-D VIBE sequence were acquired. PET was obtained for 4 minutes per bed position using a three-dimensional acquisition mode. PET images were reconstructed on 172 × 172 matrices using an iterative algorithm (ordered subset expectation maximization; two iterations and 21 subsets). Diffusion-weighted imaging (DWI) with SPAIR fat suppression and an apparent diffusion coefficient (ADC) map for the thorax and liver were obtained. Postcontrast axial 3D VIBE sequence with a dose of 0.1 mmol/kg gadoteric acid (Dotarem; Guerbet, Aulnay-sous-Bois, France) was obtained with a delay of 2 minutes. The injection rate was 3 mL/sec, followed by a 20-mL bolus of saline at the same rate. The mean examination time of PET/MR was 61.3 min ± 8.7. Table 1 summarizes the pulse parameters of each MR sequence.

FDG-PET/CT PET/CT was acquired 15.0 min ± 6.7 after completion of PET/MR using residual 18F-FDG from the initial injection. Whole body PET images were performed with the conventional protocol of 18F-FDG PET using a Biograph 40 (Siemens Medical Solutions, Knoxville, TN). LowTable 1 MR pulse sequence parameters

dose CT was performed from the head to the mid-thigh using a tube voltage of 120 kVp, 40 mA, a tube-rotation time of 0.75 s per rotation, and a pitch of 1.5. CT images were reconstructed with 5 mm thickness. Estimated effective radiation dose of CT was calculated using the results of a previous study [14]. Immediately after CT, emission PET images were acquired for 2 minutes per each bed using the three-dimensional acquisition mode. PET images were reconstructed on 200 × 200 matrices using an iterative method including algorithms for point spread function recovery and time-of-flight calculation (TrueX, Siemens Medical Solutions; two iterations and 21 subsets).

Image evaluation When PET/MR was obtained, one of three chest radiologists (J.M.G, C.M.P, or S.M.L. with 21, 13, and 7 years of experience in chest CT, respectively) assessed the whole body MR component of PET/MR and one of two nuclear medicine physicians (G.J.C or J.C.P with 19 and 13 years of experience in PET/CT, respectively) assessed the PET component of PET/MR. They were allowed to review the chest CT findings but were blinded to the PET/CT findings and the pathologic results. Each reader evaluated the tumour, node, and metastasis (TNM) stage according to the seventh edition of the International Union Against Cancer TNM classification [1]. All discrepancies in staging between MR and PET were resolved through a consensus discussion between the radiologist and nuclear medicine physician. In terms of nodal staging, we defined a lymph node as being positive when the signal intensity of the lymph node was hyperintense on T2W HASTE images and hypointense on ADC maps as well as when the FDG uptake of a lymph node was greater than the

Parameters

Dixon sequence

Coronal T1 TSE

Axial T2 HASTE

Axial 3D VIBE

DWI

Repetition time (msec) Echo time (msec) Flip angle (degrees) FOV (mm) Resolution (mm3) Bandwidth (Hz/ pixel) GRAPPA B values (mm2/s)

3.6

657

1200

3.4

6600

1.23 or 2.46 10° 500 4.1 × 2.6 × 3.1 965

8.8 130° 450 1.7 × 1.2 × 5.0 310

71 150° 400 1.5 × 1.0 × 5.0 723

1.22 9° 380 1.6 × 1.2 × 3.0 540

64 90° 380 3.0 × 3.0 × 5.0 3552

2 –

3 –

2 –

2 –

2 50, 400, 800

Note— TSE = turbo spin-echo; HASTE = half-Fourier acquisition single-shot turbo spin-echo; VIBE = volume-interpolated breath-hold examination; DWI = diffusion-weighted imaging; FOV = field of view; GRAPPA = generalized autocalibrating partially parallel acquisition

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mediastinal blood pool uptake [15] (Fig 1). We defined distant metastases as when there were hyperintense lesions on T2WI, abnormally enhancing lesions, or abnormally high FDG-uptake lesions. PET/CT was assessed by one of two nuclear medicine physicians who was blinded to the PET/MR findings of the same patient, according to the same criteria applied for the PET images of PET/MR. When a lymph node showed high attenuation (>70 HU) [5, 16] or typical benign calcification (central, laminated, popcornlike, or diffuse) on precontrast CT images, we considered the lymph node as being benign.

Statistical analysis Accuracies of PET/MR and PET/CT for TNM staging were calculated and compared using the McNemar test to investigate differences in diagnostic performance. SUVmax of primary lesions on PET/MR and PET/CT were compared using the paired t-test. Pearson correlation coefficients for SUVmax of primary lesions between PET/ MR and PET/CT were also obtained. All statistical analyses were performed using MedCalc, version 12.2.1 (MedCalc Software, Mariakerke, Belgium). Data are presented as mean ± standard deviation. A P-value of <0.05 was considered to indicate a significant difference.

Reference standard Among the 45 study patients, 35 patients underwent lobectomy and five underwent wedge resection or segmentectomy. The remaining five patients received mediastinoscopy or ultrasound-guided biopsy. Tumour stages were determined in 40 patients who underwent surgical resections. Node stages were determined in 42 patients. Metastasis stages in the 45 patients were confirmed via biopsy or follow-up imaging studies. Final confirmation of metastasis was based on pathology or multidisciplinary decision when it was impossible for pathological diagnosis. Five patients were diagnosed with metastasis via biopsy and one patient was diagnosed with metastasis on follow-up imaging study. Follow-up imaging study were performed using chest CT and brain MRI. Mean imaging follow-up period was 395.7 days (range, 153–663 days; median, 393 days). Fig. 1 A positive lymph node on PET/MR. A 13 mm left interlobar lymph node showed hyperintensity on T2-weighted half-Fourier acquisition singleshot turbo spin-echo (HASTE) image (a) and on diffusionweighted image (b = 400) (b), which was hypointense on an apparent diffusion coefficient (ADC) map (c) as well as FDGavid on PET/MR (d). This left interlobar lymph node is a typical case of a positive lymph node on PET/MR and was confirmed as a metastatic lymph node on pathology

Results The pathologic subtypes of lung cancers in the 45 patients were as follows: 32 adenocarcinomas, eight squamous cell carcinomas, two NSCLCs, one mixed small cell carcinoma and adenocarcinoma, one adenosquamous carcinoma, and one mucoepidermoid carcinoma. Tumour staging The distribution of T stages in the 40 patients confirmed via pathology were T1 in 13 patients, T2 in 21 patients, and T3 in six patients. Among the 13 T1 tumours, twelve tumours (92.3 %) were diagnosed accurately on both PET/MR and PET/CT. In one case, misdiagnosed on

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PET/MR and PET/CT, the readers evaluated a T1 tumour as T3 as an anthracotic nodule in the right upper lobe that was considered as metastasis (Fig 2). With regard to T2 tumours, the accuracy of tumour staging was 85.7 % (18/21) on both PET/MR and PET/ CT. Two of the incorrectly diagnosed tumours were located in the subpleural area with visceral pleural invasion, and the remaining one tumour showed a spiculated margin, extending to the pleura with visceral pleural invasion on pathology. As all three tumours were less than 3 cm in size, the readers reported these T2 tumours as T1. In terms of T3 tumours, the accuracy of tumour staging was 33.3 % (2/6) on both PET/MR and PET/CT. The readers misjudged metastatic satellite nodules as inflammatory nodules in two patients, and unrecognized chest wall invasions in two patients with tumours located in the subpleural area. The overall accuracies of tumour staging on PET/MR and PET/CT were 80.0 % (32/40) and 80.0 % (32/40) (P = 1.0) (Table 2).

Table 2 MR

Tumor staging accuracy in 40 patients on PET/CT and PET/

Pathology

PET/CT T1

PET/MR T2

T3

T1

T2

T3

T1 (n = 13)

12

0

1

12

0

1

T2 (n = 21)

3

18

0

3

18

0

T3 (n = 6)

0

4

2

0

4

2

and N3 in two patients. Among the 42 patients, 24 patients (57.1 %) were correctly diagnosed on PET/MR and 22 patients (52.4 %) were correctly diagnosed on PET/CT (Table 3). While the readers understaged 12 patients on PET/MR and ten patients on PET/CT, the readers conversely overstaged six patients on PET/MR and ten patients on PET/CT. There were no significant differences in the accuracy of nodal staging between PET/CT and PET/ MR (P = 0.683). Metastasis staging

Nodal staging A total of 242 nodal stations in 42 patients were evaluated through their histopathologic findings. Among them, 38 (15.7 %) nodal stations were confirmed as metastatic lymph nodes. With respect to nodal stages, there were N0 in 21 patients, N1 in seven patients, N2 in 12 patients,

Metastatic lesions in the brain, bone, liver, lung, and pleura were confirmed in six patients among 45 patients (13.3 %). Among the six patients, there was one brain metastasis in one patient, bone and liver metastases in one patient, liver metastases in one patient, and pleural metastases in three patients.

Fig. 2 T1 stage tumour misdiagnosed as T3 stage. (a) PET/MR shows a 1.9 cm solid nodule (arrow) in the right upper lobe of a 70-year-old woman. The maximum standardized uptake value (SUVmax) of the nodule was 13.5 and the nodule was confirmed as adenocarcinoma by lobectomy. (b) Another 1.2 cm nodule (arrow) at the inferior aspect of the primary lung cancer in the right upper lobe was found on the PET/MR

image. The SUVmax of the other nodule was measured to be 2.1. Furthermore, (c) the primary lung cancer and (d) the satellite nodule were seen as hypointense on apparent diffusion coefficient (ADC) maps. Therefore, the readers considered this nodule as a metastatic satellite nodule and reported the tumour stage as T3. However, this nodule was confirmed as an anthracotic lymph node on pathology

Eur Radiol Table 3 Accuracies of nodal staging in 42 patients on PET/CT and PET/MR Pathology

PET/CT N0

N1

PET/MR N2

N3

N0

N1

N2

N3

N0 (n = 21)

12

5

2

2

16

2

3

0

N1 (n = 7)

3

3

1

0

3

3

1

0

N2 (n = 12) N3 (n = 2)

3 0

3 1

6 0

0 1

3 1

4 1

5 0

0 0

Radiation dose Mean administration of 1 8 F-FDG per patient was 326.0 MBq ± 49.0 resulting in an estimated radiation dose of the PET component of PET/CT and PET/MR of 6.2 mSv ± 0.9. Mean DLP of CT scans on PET/CT was 186.3 mGy ± 36.8 resulting in an estimated effective dose of 2.8 mSv ± 0.6. Therefore, the radiation dose of PET/ MR was 31.1 % lower than that of PET/CT.

Discussion One pleural metastasis was missed on both PET/MR and PET/CT. In addition, PET/CT missed pleural metastases in one patient and a solitary brain metastasis in one patient (Fig. 3). The remaining metastatic lesions were detected on both PET/MR and PET/CT. There were no false positive cases on either PET/MR or PET/CT. Nonetheless, there were no significant differences in the accuracy of metastasis staging between PET/CT and PET/MR (P = 0.480).

Comparison of SUVmax of primary lesions between PET/CT and PET/MR The mean SUVmax of primary lesions in 45 patients was 9.0 ± 4.7 on PET/MR and 12.9 ± 6.9 on PET/CT. PET/CT showed significantly higher SUVmax of primary lesions than PET/ MR (P < 0.001). The Pearson correlation coefficient of SUVmax of primary lesions between PET/MR and PET/CT was 0.929 (P < 0.001).

Fig. 3 Solitary metastasis in the brain. (a) Postcontrast T1-weighted image shows a 6 mm enhancing lesion (arrow) in the left basal ganglia of a 62-year-old woman. The pathologic stages of the tumour and node in this patient were T3 and N1. There was no visualization of the enhancing lesion on PET. After a multidisciplinary conference, this enhancing lesion was considered as metastasis. (b) Follow-up MR image showed an increase in size of the presumed metastatic lesion (arrow) in the brain of up to 9 mm, 11 months after the operation and chemotherapy. Until this moment, there was no evidence of tumour recurrence or distant metastasis except in the brain of this patient. Thus, she underwent gamma knife surgery for control of the brain metastatic lesion

In our study, the accuracies of PET/MR for TNM staging in patients with NSCLC were not significantly different from those of PET/CT as in previous studies [9, 11, 12]. Considering the equivalent performance of PET between PET/MR and PET/CT, MR is a key component that can show potentially better diagnostic performance than PET/ CT [10, 17]. For this, it is necessary that the study population includes many difficult cases for staging, for which MR imaging can help, such as infiltration of adjacent structures or brain metastasis. This implies that PET/MR may indeed perform better in patients with unresectable, higher-stage disease than in patients with resectable disease. Given that PET/MR is not superior to PET/CT for NSCLC staging, longer examination time and higher cost of PET/MR in addition to inherent demerits of MR (wide contraindications) should be overcome to successfully implement PET/MR in routine clinical practice. In terms of T staging, T1 and T2 stages comprised 85.0 % of the study population with an accuracy of 88.2 % in our study. Although there were two primary lung cancers involving the chest wall in our study, readers were not able to correctly differentiate T3 from T2 as there was no definite visualization of invasion on MR. Compared to Yi et al.’s study [5], the accuracies of T1 and T2 staging between our studies were similar (T1 stage, 92.3 % in our study vs. 90.6 %; T2 stage, 85.7 % in our study vs. 89.9 %) while the accuracy of T3 staging was lower in our study (33.3 % in our study vs. 50.0 %). We believe that the difference in regards to the accuracy of T3 staging may have resulted from the small number of patients in our study. As for nodal staging, previous studies have found it challenging for imaging studies to correctly diagnose the N stage. In this regard, MR has recently garnered much attention as a potential problem-solver. Heusch et al. [11] reported that PET/MR correctly diagnosed the nodal stage in 20 of 22 patients (90.9 %) while PET/CT correctly diagnosed the nodal stage in 18 of 22 patients (81.8 %), resulting in no significant difference. Our study also found that there were no statistical differences, although PET/MR

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included dedicated pulmonary MR sequences. Moreover, compared with previous studies [5, 11, 18], our study showed lower accuracies (52.4-57.1 %) for nodal staging on both PET/MR and PET/CT. This may be because readers were supposed to interpret PET/MR or PET/CT on the same day after PET/MR or PET/CT was performed. This condition was the same as in routine practice and readers are sometimes likely to experience limited time and consensus for interpretation. Other causes such as low experience of observers for PET/MR or the characteristics of study population can also be considered. With regard to distant metastases, the incidence of metastasis was 13.3 % (6/45) in our study. According to previous two studies [5, 8], which included patients with lung cancers that were considered candidates for surgical resection, 20.1 % and 19.7 % of patients had metastatic lesions. The results of our study in which one brain metastasis was missed on PET/ CT corresponds well with these previous studies [5, 8], which depicted the weakness of PET/CT in detecting brain metastasis. In regards to SUVmax, PET/MR showed significantly lower SUVmax of primary lesions than PET/CT in our study. The acquisition of PET/MR prior to PET/CT in our study can be one of the possible explanations for SUV results. The correlation of SUVmax of primary lesion on PET/MR and PET/CT was 0.929 with statistical significance (P < 0.001) in our study. This result also well corresponds with the results of previous studies [10, 11, 19]. However, there is still needed development of a robust and uniform protocol for measurement of SUVmax in PET/MR and to ensure the interchangeability and comparability between PET/MR and PET/CT during initial workup or follow-up. Finally, with respect to radiation dose, the estimated radiation dose of PET/MR was 31.1 % lower than that of PET/CT in our study. Given that recent studies [20, 21] revealed that even a relatively low irradiation of medical imaging can result in a small but absolute risk for excess cancer, PET/MR has a substantial advantage over PET/CT, particularly for the younger population. Our study has several limitations. First, the number of patients with higher stage of lung cancer was not large because only patients with clinically resectable status were included. Second, a multi-reader comparison was not performed. Although evaluation of multi-readers may provide more reliable data, we believe that the condition of our study in which multi-readers randomly evaluated the imaging studies can better reflect routine clinical practice and demonstrate the realistic diagnostic performance of PET/MR and PET/CT. Third, readers had access to contrast-enhanced CT because PET/CT is usually performed without contrast administration in our country. A direct comparison between contrast-enhanced PET/MR and PET/CT may have been a better approach.

In conclusion, this study demonstrated that PET/MR in combination with contrast-enhanced CT was comparable to PET/CT in the preoperative staging of NSCLC, while reducing the radiation exposure to patients.

Acknowledgments The scientific guarantor of this publication is Prof. Jin Mo Goo. The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. This study has received funding by grant from the Guerbet Korea Research Fund. No complex statistical methods were necessary for this paper. Institutional Review Board approval was obtained. Written informed consent was obtained from all subjects (patients) in this study. Methodology: prospective, diagnostic or prognostic study, performed at one institution.

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